Journal of Labetted Compacnds and Radiopharmaceuticals - V O ~ Xv

SYNTHESIS OF GWIC ACID ( - 1 4 ~ ~ ~ ~ )

CH I. Kozdk', L. Kronrbd*, M. Proch6zka

'Institute of Biophysics , Charles University Prague 2, Salmovska 3, CSSR

*Institute of Nuclear Research Rez by Prague, CSSR.

*Department of Organic Chemistry,

Received February 15, 1977 Revimd January 24, 1978

Charles University, Prague 2, Albertov 2030, CSSR.

SUMHARY

A series of reactions was elaborated for the transformation of 1,2,3-trimethoxybenzene into pllic acid-14C02H. The intermediate l-bromo-3,4,5- trimethoxybenzene was prepared by nitration, reduction, diazotization, and decomposition of the diazonium salt in the presence of cuprous bromide. The halide-exchange reaction of the aryl bromide with butyl lithium, decomposition of the inter- mediate lithio derivative with 14C02, and demethyl-

ation, led to gallic a ~ i d - ~ ~ C o ~ H .

Key Words : Gallic a~id-~~C0OH; eemimicorsyntherie .

INTRODUCTION

In order to study the metabolism and distribution of various

tannin-like compounds it was necessary to prepare selectively labelled

gallic acid.

and biological properties, it was possible to consider labelling with

either 3H or 14C atoms.

3,4,5-trihpdroxybenzoic acid -14C00H, because labelling with tritium

usually leads to non-specifically labeled products.

chemical sequence minimizes the number of reaction stepe with radio-

active material and incorporates readily available starting materials.

With respect to the requirements for maintaining chemical

A method was devised for the synthesis of

The devised

The intermdiate l-bromo-3,4,5-trimethoxybenzene cannot be 0362-480 3/78/0015-0401~0 1 *03 ~1978 by JOW wiley & Sons Ltd.

901

402 I. Koahk, L. e o n & and M. fiochhaka

prepared chemically pure (TLC and GLC) and in good yield, via the bro-

mination of 1,2,3-trimethoxybenzene, 1,2,3-trihydroxybenzene or 1,3-

dimethoxy-2-hydroxybenzene followed by selective debromination of the

resulting polybromo derivatives to mono-bromo compounds, although

these reactions are described in the literature (1,2). Bromination

with pyridinium bromide perbromide or dioxane dibromide did not yield

the desired product.

according to the methods of Hunsdiecker (3) did not prove to be

feasible.

The degradation of the silver salt of the acid

Methods for the conversion of 3,4,5-trimethoxyaniline (4.5)

into 1-halo or 1-cyano- 3,4,5-trimethoxybenzenes were found to be suit-

able procedures. Accordingly, diazotization of the aniline followed by

cuprous halide (or cyanide) mediated decompositions of the intermediate

diazonium salt provided high product yields. The reaction of l-iodo-

3,4$-trimethoxybenzene with cuprous cyanide in dimethylformamide gave

the nitrile in 80% yield.

reaction of imide ion with hydroxyl groups generated during demethyla-

tion, thus the nitrile was hydrolyzed in alkali medium and then the

protecting methyl groups were removed with hydrogen iodide.

lithium procedure was used for the synthesis of the labelled gallic acid

because the preparation of Cu14CN results in a loss of activity at this

stage.

Galloylgallic acid can result by the

A butyl

The l-brom0-3,4,5-trimethoxybenzene does not easily react with

magnesium to form the Crignard compound.

ation are observed when using highly active magnesium prepared by

potassium metal reduction of magnesium salts.

reaction of the aryl bromide with butyl lithium in ether resulted in an

intermediate lithio derivative. Subsequent reaction with 14C02 , generated from Ba

Halogen reduction and demethyl-

The halide-exchange

14

Acidic demethylation reactions were complicated by the ready de-

CO.,, provided the labelled gallic acid derivative.

carboxylation of the resulting gallic acid.

trifluoride, pyridinium hydrochloride, or an aqueous solution of hydrogen

Aluminium bromide, boron

4 03

iodide were found t o be unsuitable demethylation reagents.

y ie ld of demethylated product was obtained with 45% hydrogen iodide i n

ace t i c acid at the optimum thermal conditions.

An 80%

EXPERIMENTAL

Preparation of non-radioactive compounds

1,2.3-Trimethoxybenzene 11.

pyrogallol (I) with dimethyl s u l f a t e i n a lka l ine medium (6).

y i e ld of product melting a t 47OC was realized.

l-Nitro-3,4,5-methoxybenzene 111.

with the l i t e r a t u r e (4,7) by the n i t r a t i o n of G.

from ace t i c acid provided a 42% y ie ld of material melting a t 100°C.

3,4,5-Trimethoxyaniline IV.

acid containing 2.5 g of 10% palladium on charcoal was hydrogenated a t

ambient tempreature and pressure.

took place a f t e r 6 hrs. The ca t a lys t w a s removed by f i l t r a t i o n under an

i n e r t atmosphere and the so lu t ion w a s concentrated t o a volume of 50 mL.

After ac id i f i ca t ion with hydrochloric acid and d i lu t ion with 250 mL of

d ie thyl e ther , the cntde product was collected.

hydrochloride of E w a s 8,8 g (87%).

l-Bromo-3,4,5-trimethox~benzene V.

water and 100 mL 57% hydrobromic ac id were heated on a water bath t o 7OoC.

After cooling t o -5OC with s t i r r i n g , a so lu t ion of 20,7 g of sodium

n i t r i t e i n 100 mL water was added.

15 min., excess n i t rous acid w a s decomposed by the addition of urea u n t i l a negative t e s t with potaseium iodide-starch paper was observed.

A cooled (OOC) f resh ly prepared so lu t ion of cuprous bromide (86.5 g i n

250 mL of 57% hydrobromic acid) was added t o the reaction mixture.

composition of the diazonium salt was car r ied out a t 60 - 70°C u n t i l

the evolution of nitrogen gas ceased. The reaction mixture was extracted

with chloroform, washed with 10% sodium hydroxide, and dr ied over calcium

chloride.

of the d i s t i l a t e provided

Compound I1 was prepared by the reaction of

A 66%

Compound I11 was obtained i n accordance

Three r ec rys t a l l i za t ions

A mixture of 10 g of III i n 200 mL of a c e t i c

The theo re t i ca l absorption of hydrogen

The weight of the

A suspension of 8,8 g of in 300 mL

The mixture was s t i r r e d a t -5OC f o r

De-

Fractional d i s t i l l a t i o n (147.5 - 149OC a t 11 t o r r ) and TLC

g (74%) of material melting a t 79 - 8OoC.

A melting point of 78OC is recorded (1) f o r the product obtained v i a

the methylation of 1,3-dimethoxy-2-hydroxy-5-bromobenzene.

Preparation of labe l led de r iva t ives

Trimethylgal l ic acid - 1 4 C V I . To a cooled (-5OC) and s t i r r e d so lu t ion

of 1.00 g (4.04 mmol) of !in 30 mL of anhydrous e ther , under a blanket

of argon, w a s added 5 mL of 0.85 N buty l l i th ium in benzene (4.25 mmol).

The r e su l t i ng mixture was s t i r r e d a t -5OC f o r 15 min and then t h e

mixture w a s cooled t o -75OC i n a dry-ice e thanol bath.

vessel was flushed with argon and evacuated.

centrated Sul fur ic ac id and 1.32 g (6.70 mmol) of powdered barium

carbonate - 1 4 C (200 mCi, s p e c i f i c a c t i v i t y 30 mCi/mmol) i n a 25 mL

f l a sk was heated t o 12OoC. The evolved gaseous carbon dioxide - 14C

was passed in to the f l a s k containing the s t i r r e d e the ra l so lu t ion of

l i t h i o compound.

was allowed t o warm t o ambient temperature over a t i m e period of about

one hour.

through 50 mL of 30% barium hydroxide so lu t ion .

was t rea ted with 30 mL of 10% NaOH solu t ion .

separated, ac id i f i ed with s u l f u r i c ac id t o pH 2.0, and t he product w a s

extracted with two 30 mL port ions of e ther .

ex t r ac t s were washed with water and dr ied over anhydrous magnesium

su l f a t e .

47.3 mCi) of c rys t a l l i ne , l i g h t yellow colored product melting a t 167-goC,

f o r a 48% weight y i e ld and a 23.6% a c t i v i t y y ie ld .

of the crude mater ia l was 24.38 mCi/mmol .

g a l l i c acid - 14C w a s checked by means of TLC (S i lu fo l W 254) by

developing with benzene/methyl a lcohol (95:5). Visual izat ion of the

TLC p l a t e under u l t r av io l e t l i g h t gave an Rf f o r t he product

and t h i s spot contained 96.0% of the t o t a l a c t i v i t y i n the chromatogram.

Gallic ac id - 1 4 C VII.

i n 7 mL of g l ac i a l acetic ac id ( ana ly t i ca l grade) containing 7 mL of 57%

hydrogen iodide so lu t ion (Merck, r e d i s t i l l e d ) w a s heated under reflux

The react ion

A mixture of 4 mL of con-

The cooling ba th was removed and the reac t ion mixture

The unreacted gaseous carbon dioxide - 14C was bubbled

The reac t ion mixture

The aqueous l a y e r was

The combined e the ra l

Evaporation under reduced pressure provided 0.41 g (1.94 mmol,

The s p e c i f i c a c t i v i t y

The pur i ty of the t r imethyl

of 0.7

A mixture of 0.41 g (1.94 l m r ~ l , 47.3 mCi) of VI

Gallic Acid (-14COOHl 405

f o r 4 hrs .

reduced pressure.

t r i t u r a t e d i n 20 mt of water, the s o l i d s were f i l t e r e d , and the water

w a s evaporated under reduced pressure.

more times.

one spot a f t e r the th i rd evaporation.

manner contained t races of iodine which made synthe t ic react ions

impossible u n t i l fu r the r pur i f ica t ion .

r ec rys t a l l i zed twice from 2 mt of water t r e a t i n g with charcoal, thus

giving a y ie ld of 0.080 g (0.47 -1) of white colored product which

had a 1 4 C a c t i v i t y of 11.5 mCi .

The reac t ion mixture w a s evaporated t o dryness a t 4OoC under

The r e su l t i ng brownish-black c r y s t a l l i n e residue was

This procedure was repeated two

The product had a l i g h t brown color and TLC showed only

The g a l l i c acid prepared i n t h i s

The g a l l i c acid - 1 4 C was

CONCLUSION

A method was elaborated f o r t h e semimicro synthes is of l abe l l ed

g a l l i c ac id , - 14C02H. The pu r i ty of t he f i n a l product was s u f f i c i e n t

f o r b io logica l t e s t ing a s w e l l as f o r continued synthe t ic e laborat ion.

The l abe l l ed g a l l i c ac id was prepared i n about 25% iso topic y ie ld .

mass y i e l d of t he pure product w a s about 15% and the s p e c i f i c a c t i v i t y

corresponded t o the s p e c i f i c a c t i v i t y of the i n i t i a l barium carbonate.

The

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